Metalation of alkyl side chains of alkyl pyridines,alkyl quinolines and alkyl isoquinolines

ABSTRACT

Metalating alkyl side chains of alkyl pyridines, alkyl quinolines and alkyl isoquinolines by means of certain organometal compounds, exemplified by alkali metal substituted furan compounds and alkali metal substituted methylpyrrole, and 2-thienyllithium. The metalation reaction advantageously is carried out in the presence of an ethereal solvent which forms a stable coordination complex with the metalated compound.

United States Patent [151 3,691,174 Screttas [451 Sept. 12, 1972 [s41 METALATION 0F ALKYL sum [561' References Cited CHAINS OF ALKYL PYRIDINES,

ALKYL QUINOLINES AND ALKYL ISOQUINOLINES Inventor: Constantinos G. Screttas, 13 Antinoros Street, Athens, 516, Greece Filed: Aug. 7, 1970 Appl. No.: 62,198

Related U.S. Application Data Continuation-impart of Ser. No. 646,208, June 15, I967, abandoned.

US. Cl ..260/290 R, 260/283 R, 260/297 R Int. Cl. ..C07d 31/20 Field of Search ....260/290 R, 283 R OTHER PUBLICATIONS Klingsberg, Pyridine & Derivatives, Part Two, Interscience Publishers, Pages 422- 425, (1961) OD 401 K5 C.2

lngram et al., Chem. Abstracts, Vol. 62, 1677- 1679 (Jan. 1965) Primary Examiner-Alan L. Rotman Attorney-Wallenstein, Spangenberg, Hattis & Strampel [57] ABSTRACT Metalating alkyl side chains of alkyl pyridines, alkyl quinolines and alkyl isoquinolines by means of certain organometal compounds, exemplified by alkali metal 13 Claims, No Drawings METALATION F ALKYL SIDE CHAINS 0F ALKYL PYRIDINES, ALKYL QUINOLINES AND I ALKYL ISOQUINOLINES This application is a continuation-in-part of application Ser. No. 646,208, filed June 15, 1967, now abandoned.

BACKGROUND OF THE INVENTION metalation practices have have not been satisfactory due to the tendency of the metalating agents to attack the pyridine ring of the compound to be metalated. Thus, for example, in preparing picolyllithiums from the corresponding picolines, utilizing phenyllithium as the'metalating agent, substantial quantities of phenyl-- pyridines are formed due to side reactions between the phe'nyllithium and the pyridine rings. The formation of the phenylpyridines'not only adversely affects yields but also adversely affects the purity of the desired picolyllithiums.

SUMMARY OF THE INVENTION In accordance with the present invention, there is provided a method of metalating alkyl pyridines, alkyl quinolines, and alkyl isoquinolines, which enables substantially exclusive side chain metalation to be obtained. This result is achieved by means of the use of certain organometallic metalating agents selected from the group consisting of alkali metal thienyl, furyl, lmethylpyrryl and l-methylindole compounds. Yields, based on metalating agent, are commonly quantitative or nearly so. In accordance with the preferred practice of the present invention, the metalation reaction is carried out in the presence of anether which may form a normally solid complex with the metalated compound. The complexes thus obtained are highly stable for prolonged periods, frequently several months, but in some cases as much as one year, at refrigeration temperatures. They have a high content of active alkali metal per unit weight. Furthermore, they can beformed into solutions which facilitate their handling and shipment.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The method of the present invention can be employed to provide metalation products of monoand polyalkylated pyridines, monoand polyalkylated quinolines and polyalkylated isoquinolines. The alkyl substituents on the compound to be metalated may contain from one to 16 carbon atoms, with optimum results being achieved with compounds having one or more alkyl substituents thereon containing from one to five carbon atoms. Examples of compounds which undergo substantially exclusive side chain metalation by the method of the present invention are picolines such as 2- methylpyridine, 3-methylpyridine and 4-methylpyridine; lutidines exemplified by 2,4-dimethylpyridine and 2,6-dimethylpyridine; collidines, specific examples of which are 2,3,4-trimethylpyridine and 2,4,5-

trimethylpyridine; 2-ethylpyridine; 2-butylpyridine; 2- methyl-4-ethylpyridine; 2,4-diethylpyridine; 2-hexylpyridine; 2octylpyridine; 2-hexadecylpyridine; quinolines such as Z-methylquinoline, 4-methylquinoline, 2- dodecylquinoline, 2-methyl-4-dodecylquinoline and 2,4-dimethylquinoline; and isoquinolines, examples of which are l-metylisoquinoline, l-methylisoquinoline, l-decylisoquinoline, l,3-dimethylisoquinoline, l ,4- dimethyl-isoquinoline, l-methyl-3-ethylisoquinoline; and the like.

As illustrative of the unique capabilities of the method of this invention is, for example, the preparation of the compound l,l-dicyclohexyl-2-(2-pyridyl)- ethanol and its hydrochloride, by reaction of 2-picolyllithium with dicyclohexyl ketone. This compound has utility in the preparation of l-(2-piperidinyl)-2,2- dicyclohexylethene,

a compound known to be effective in the treatment of anginaldisease. The method of the present invention for producing side-chain metalation products may also be used to advantage in the preparation of polyalkali metal substituted compounds from the corresponding polyalkylated pyridines, quinolines and isoquinolines. The side-chain metalated compounds have a variety of utilities. Thus, for instance, 4-picolyllithium is used in the preparation of 2-cycloalkyl-l,3-di(4-pyridyl)-2- propanols which are useful for the treatment of diseases caused by metabolic failures of enzyme systems (U.S. Pat. No. 3,309,375); and is used in the preparation of l,3-dipyridyl-2-isopropylpropanes which, by reduction, form l,3-dipiperidyl-2-isopropylpropanes which possess antidepressant and cardiovascular properties (British Patent No. 1,106,028); 2-picolyllithium is used in the synthesis of the alkaloid pelletierine which is useful against tapeworms in dogs (Merck Index, Vol. 8, p. 787); and see, also, US. Pat. No. 3,400,131 for other uses of picolyl-metal compounds.

The metalating agents having utility in the practice of the method of the present invention, as indicated hereinabove, can be characterized as belonging to:

Alkali metal substituted heteroaromatic compounds represented by the following formulas:

Tl s

(II) M (III) n f (EH:

in which M is an alkali metal (Na, K, Li, Rb, Cs).

While, as stated, M in all three of the above groups may be any of the alkali metals sodium, potassium, lithium, rubidium and cesium, it is preferred that M be lithium or sodium.

Exemplary of specific metalating agents that are useful in carrying out the method of the present invention are: 2-furyllithium, 2-( l-methyl) l-pyrryllithium, 2- thienyllithium, 2-thienylsodium. Of the foregoing, 2-furyllithium and 2-thienyllithium are especially preferred as the metalating agent.

The ethers utilized in the practice of the method of this invention to form coordination complexes with the side chain metalation products can be selected from a wide group. Generally speaking, the ethers having utility for this purpose can be characterized as those ethers which are capable of forming a normally solid complex with the metalated compound. Examples of ethers satisfying this criterion are linear alkyl ethers such as dimethyl ether, methyl ethyl ether, diethyl ether, ethyl n-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether and cyclic alkyl ethers represented by tetrahydrofuran (THF), tetrahydropyran (THP), 1,4-dioxane, 7-oxa[2.2.l] bicycloheptane (OBH), and the like. The quantity of ether employed in the reaction mixture is variable. The general objectives of the present invention are fulfilled when the ether is used in an amount such that at least one molecule of the ether per atom of alkali metal is present in the reaction mixture.

in carrying out the method of the present invention, generally speaking, the metalating agent is dissolved in a mixture of the appropriate ether, as hereinbefore described, with an inert organic solvent, particularly a hydrocarbon solvent, and added to the compound to be metalated. The reverse method of addition, that is, addition of the compound to be metalated to a solution of the metalating agent, also gives high yields of the sidechain metalation product. Various inert organic solvents can be used such as, for example, benzene, pentane, hexane, heptane, octane, isooctane, and the like, as well as mixtures thereof. The volume of inert organic solvent used can be varied. From the standpoint of practical considerations, the volume of the inert solvent employed should be maintained at levels which will not impede or prolong recovery of the side-chain metalation product. However, the volume of the inert solvent should desirably exceed that of the ether employed to effect formation of a coordination complex between the ether and the metalation product, thereby to maintain the metalating agent and the product in solution. In the former case, only partial solution is necessary for its use as a metalating agent. To these ends, an excess of the inert solvent over the ether of the order of from about 2 to 10 percent, usually 3 to 5 percent, by volume, is advantageously used.

The following specific examples are given to illustrate the practice of the method of the present invention. It will be understood that numerous other examples will readily occur to those skilled in the art in the light of the novel guiding principles and teachings disclosed herein. All temperatures are in degrees C.

EXAMPLEI To 30 ml of a l.7 N solution of 2-thienyllithium in benzene-tetrahydrofuran was added 10 ml of 2-methylpyridine which had been dried over barium oxide. The resulting mixture was stirred at room temperature for 12 hours to yield a solution containing the desired picolyllithium. The picolyllithium can be separated in accordance with known practices. One such method is set forth in Example lll.

To determine the nature and yield of the picolyllithium, 9 g of benzophenone dissolved in 50 ml of diethyl ether was added to the reaction mixture. Stirring was continued for 3 hours. The reaction mixture was then hydrolyzed, the organic layer separated and the product was freed from solvent by evaporation by dryness in vacuo. The product, l,l-diphenyl-2-(2-pyridyl)- ethanol, after steam distillation, weighed 13.5 g, (98 percent), m.p. l35l45. After one recrystallization from boiling hexane it melted at 15 l-l52.

EXAMPLE II To ml of a 1.7 N solution of 2-thienyllithium in benzene-tetrahydrofuran was added 20 ml of 4-methylpyridine. The resulting mixture was stirred overnight to yield a solution containing the desired picolyllithium. As in the case of Example I, the picolyllithium can be separated as set forth in Example IV.

To determine the nature and yield of the picolyllithium obtained, 30 g of benzophenone dissolved in 50 ml of diethyl ether was added to the reaction mixture containing the picolyllithium. Stirring was continued until the color of the mixture turned light blue. The reaction was worked up as described in Example I to give 36 g (94 percent) of l,l-diphenyl-2-(4-pyridyl)-ethanol, m.p. l35l40. The recrystallized material melted at -162.

EXAMPLE [I] isolation and Characterization of the Gamma- Picolyllithium-THF Complex To a mixture of 0.2 mol of 2-thienyllithium in 40 ml of benzene and 16 ml of tetrahydrofuran was added at once 20 ml (approximately 0.2 mole) of gammapicoline. The resulting mixture was stirred under nitrogen for about 48 hours. During this period of time the mixture turned green and a green precipitate was formed. This precipitate was isolated by filtration in a dry argon atmosphere. The precipitate was washed with dry pentane, dried in a stream of argon and analyzed as follows: A 1.8807 g sample was hydrolyzed with ca 20 ml of distilled water and the hydrolyzate was pH-titrated with 0.5 N hydrochloric acid. The titration curve (pH against milliliters of 0.5 N HCl added) exhibited two breaks, one at about pH 7.8 (endpoint for lithium hydroxide neutralization) and the other at about pH 2.6 (endpoint of gamma-picoline neutralization); these two breaks occurred at 21 .4 ml and 41.6 ml respectively indicating the correspondence of one lithium atom per one molecule of picoline. Another sample (ca 1.0 gram) was quenched with 3 ml of sec-butyl alcohol. An aliquot of this solution was analyzed by vapor phase chromatography which indicated that one molecule of tetrahydrofuran corresponded to one molecule of gamma-picoline. Hence, in the said complex, the ratio is 1 Li atomzl molecule of picolinezl molecule of tetrahydrofuran.

EXAMPLE IV To 30 ml of 1.7 N solution of Z-furyllithium in tetrahydrofuran-benzene was added mol of 2- methylpyridine. The resulting mixture was stirred for l2 hours to yield a dark green solution of a-lithio-Z- methylpyridine.

To determine the nature and yield of the picolyllithiums, 9 g of dicyclohexyl ketone dissolved in ml of tetrahydrofuran was added to the reaction mixture and stirred for 3 hours. The reaction mixture was then hydrolyzed and washed with ether; the organic layer was separated, washed once with water and dried. Anhydrous gaseous hydrogen chloride was added to the solution at l0-l5 until'no more was absorbed; the resultant precipitate was collected and dried, giving 13.2 g (92 percent) of l,l-dicyclohexyl-2(2-pyridyl) ethanol hydrochloride, m.p. l85-6. After one recrystallization from 2-propanol, it melted at 188.

EXAMPLE V To ml of a 1.7 N solution of 2-lithio-l-methylpyrrole in tetrahydrofuran-benzene was added 10 ml of 2- methylpyridine. The resultant mixture was stirred for 4 hours to yield a solution of a-lithio-2-methylpyridine. This solution was then reacted with dicyclohexyl ketone as described in Example V and the product was isolated, giving 13.0 g (88 percent) of l,l-dicyclohexyl-2( 2-pyridyl)ethanol hydrochloride, m.p. l856.

EXAMPLE Vl To 60 ml of a 1.7 N solution of 2-lithio-l-methyl-indole in tetrahydrofuran-benzene was added 20 ml of 2- methylpyridine. The resultant mixture was stirred for .12 hours to yield a solution of a-lithio-Z-methylpyridine. This solution was then reacted with dicyclohexyl ketone as described in Example V and the product was isolated, giving 13.4 g (95 percent) of 1,1- dicyclohexyl-2(2-pyridyl) ethanol hydrochloride, m.p. l85-6.

EXAMPLE Vll To 80 ml of a 1.7 N solution of Z-Ihienyllithium in benzene-tetrahydrofuran was added 20 ml of Z-methylpyridine. The resulting mixture was stirred for 12 hours to yield a dark green solution of a-lithio2-methylpyridine.

To determine the nature and yield of the picolyllithium, 30 g of benzophenone dissolved in 50 ml of tetrahydrofuran was added to the reaction mixture. Stirring was continued for 3 hours; then the product was hydrolyzed, the organic layer separated and dried, and the low-boiling solvents removed, under vacuum, to dryness. The product, l,l-diphenyl-2(2- pyridyl)ethanol, weighed 12.9 g (92 percent), m.p. l489. One recrystallization from 2-propanol gave white crystals, m.p. l52-3.

EXAMPLE Vlll This example shows an illustrative use of the solid apicolyllithium THF complex. 34.2 g (0.20 mole) of a solid (1:1) complex of a-picolyllithium THF was dis- Then, 36.2 g (0.20 mole) of benzophenone,-dissolved in 50 ml of THF, was added dropwise to the a-picolyllithium solution. An exothermic reaction occured. At the end of theaddition, the reaction mixture was stirred for 3 hours at room temperature. Then the mixture was hydrolyzed with ice water, the organic layer was separated and dried, and the low-boiling solvents were removed, under vacuum, to dryness. The product, l,ldiphenyl-2(2-pyridyl)ethanol, weighted 46.7 g (87 percent), m.p. l489.

lclaim:

1. in a method of metalating an alkyl side chain of a member selected from the group consisting of alkyl pyridines, alkyl quinolines and alkyl isoquinolines in which the alkyl group contains from one to 16 carbon atoms, the step which consists of effecting said metalating in an ethereal solvent by means of an organometal (I) (H) U (in. on.

(V) OR (VI) OR (VII) OR (VIII) OR M R10 OR (IX) M where M is an alkali metal of the group of sodium, potassium, lithium, rubidium and cesium.

2. The method of claim 1, in which alkyl in said alkyl pyridines, alkyl quinolines and alkyl isoquinolines contains from one to five carbon atoms.

3. The method of claim 2, in which M is lithium.

4. The method of claim 2, in which the ethereal solvent is present in an amount of at least about one molecule per atom of alkali metal.

5. The method of claim 4, in which the ethereal solvent is one which forms a normally solid complex with said side chain metalated compound.

6. The method of claim 5, in which the ethereal solvent is tetrahydrofuran.

7. The method of claim 6, in which the metalating reaction medium also contains a liquid hydrocarbon which is inert to said metalating agent.

8. The method of claim 7, in which the liquid hydrocarbon comprises benzene, said benzene exceeding in volume that of the tetrahydrofuran.

9. The method of claim 4, in which the alkyl pyridine is a picoline.

10. The method of claim 8, in which the alkyl 

2. The method of claim 1, in which alkyl in said alkyl pyridines, alkyl quinolines and alkyl isoquinolines contains from one to five carbon atoms.
 3. The method of claim 2, in which M is lithium.
 4. The method of claim 2, in which the ethereal solvent is present in an amount of at least about one molecule per atom of alkali metal.
 5. The method of claim 4, in which the ethereal solvent is one which forms a normally solid complex with said side chain metalated compound.
 6. The method of claim 5, in which the ethereal solvent is tetrahydrofuran.
 7. The method of claim 6, in which the metalating reaction medium also contains a liquid hydrocarbon which is inert to said metalating agent.
 8. The method of claim 7, in which the liquid hydrocarbon comprises benzene, said benzene exceeding in volume that of the tetrahydrofuran.
 9. The method of claim 4, in which the alkyl pyridine is a picoline.
 10. The method of claim 8, in which the alkyl pyridine is a picoline.
 11. The method of claim 2, in which the metalating compound is 2-furyllithium.
 12. The method of claim 2, in which the metalating compound is 2-lithio-1-methylpyrrole.
 13. The method of claim 2, in which the metalating compound is 2-lithio-1-methylindole. 